Functional genomics of complex cancer genomes.

Cancer functional genomics is the study of how genetic, epigenetic, and transcriptional alterations affect cancer phenotypes, such as growth and therapeutic response. Here, we comment on how, taking advantage of next generation sequencing, functional genomics, often combined with systems biology approaches, has revealed novel cancer vulnerabilities beyond the original paradigm of one gene-one phenotype

Synchronous primary papillary breast cancer, medullary thyroid carcinoma and neuroendocrine tumor in postmenopausal woman.

Multiple endocrine neoplasia are syndromes involving two or more endocrine tissues, often correlated to RET proto-oncogene mutations. We herein present the first reported case of a 57-years-old woman with three synchronous primary cancers of breast (papillary), thyroid (medullary) and pancreas (neuroendocrine), the latter with liver metastasis. The patient first underwent surgery for papillary breast cancer with axillary lymph nodes metastases. A staging whole body computerized tomography (CT) showed a right lateral cervical lymph node, pancreatic inhomogeneity, peri-pancreatic nodes and a single liver metastasis. The poor response to an antracycline and taxane-based chemotherapy, the good performance status of patient, and associated symptoms, suggested a different origin for pancreatic and hepatic lesions. A careful re-evaluation of clinical history, an octreotide-labeled scan and an immunohistochemical analysis, on both hepatic and pancreatic tissues and on laterocervical lymph node, determined the diagnosis of synchronous papillary breast cancer, pancreatic neuroendocrine tumor (pNET) with liver metastasis and an occult medullary thyroid carcinoma in a patient who had proto-oncogene RET wild type

A case of clinical worsening after stereo-electroencephalographic-guided radiofrequency thermocoagulation in a patient with polymicrogyria

: Radiofrequency thermocoagulation (RF-TC) is a wide-used procedure for drug-resistant epilepsy. The technique is considered safe with an overall risk of 1.1% of permanent complications, mainly focal neurological deficits. We report the case of a patient with drug-resistant epilepsy who complained of immediate seizure worsening and an unexpected event seven months following RF-TC. A 35-year-old male with drug-resistant epilepsy from the age of 18 years underwent stereoelectroencephalography (SEEG) implantation for a right peri-silvian polymicrogyria. He was excluded from surgery due to extent of the epileptogenic zone and the risk of visual field deficits. RF-TC was attempted to ablate the most epileptogenic zone identified by SEEG. After RF-TC, the patient reported an increase in seizure severity/frequency and experienced episodes of postictal psychosis. Off-label cannabidiol treatment led to improved seizure control and resolution of postictal psychosis. Patients with polymicrogyria (PwP) may present with a disruption of normal anatomy and the co-existence between epileptogenic zone and eloquent cortex within the malformation. RF-TC should be considered in PwP when they are excluded from surgery for prognostic and palliative purposes. However, given the complex interplay between pathological and electrophysiological networks in these patients, the remote possibility of clinical exacerbation after RF-TC should also be taken into account

Development and application of a MLST panel for the identification of informative polymorphisms in Leishmania infantum strains in the Mediterranean region

Background. Leishmaniasis is a zoonotic disease endemic in the Mediterranean region, where the causative agent of human and canine infection is Leishmania infantum. The spread of leishmaniasis is associated with population movements, ecology of phlebotomine vectors, and reservoir host. We used multilocus sequence typing (MLST) to explore the genetic variability of L. infantum strains in the Mediterranean region, including the borderline territory of Pantelleria island, and identify informative polymorphisms for rapid identification of genotypes through high-resolution melt (HRM)-based assays. Material and Methods. A customized sequencing panel targeting 14 housekeeping genes was designed and MLST analysis was performed using the Ion Torrent S5 on 9 L. infantum strains/isolates: 5 canine isolates (3 from Pantelleria Island and 2 from central Italy), and 4 human isolates/strains from Tunisia, France, central and southern Italy. MLST results and in silico analysis of sequences available in Genbank allowed to select two informative polymorphisms on ME and GPI genes (390T/G and 1834A/G, respectively) used to develop two HRM-based assays for fast screening of 28 clinical samples. Results. The MLST analysis identified a single L. infantum clonal complex regardless of the geographic origin or host (human or canine), except for the human isolate from central Italy that showed polymorphisms in 11 out of 14 housekeeping genes, and clustered independently in a molecular phylogenetic analysis. Successively, the screening through HRM-based assays of 28 clinical samples from central/south Italy and Pantelleria island allowed to identify 6 diploid sequence types (DSTs). Interestingly, the sequence type 390T/1834A was found only in Pantelleria island (prevalence 75%). Conclusion. This study represents a description of the genetic variability of L. infantum through a first approach based on MLST and then by HRM analysis on selected polymorphisms. The HRM assays could be used as fast and cheap tools for epidemiological surveillance of L. infantum

High-resolution deconstruction of evolution induced by chemotherapy treatments in breast cancer xenografts.

The processes by which tumors evolve are essential to the efficacy of treatment, but quantitative understanding of intratumoral dynamics has been limited. Although intratumoral heterogeneity is common, quantification of evolution is difficult from clinical samples because treatment replicates cannot be performed and because matched serial samples are infrequently available. To circumvent these problems we derived and assayed large sets of human triple-negative breast cancer xenografts and cell cultures from two patients, including 86 xenografts from cyclophosphamide, doxorubicin, cisplatin, docetaxel, or vehicle treatment cohorts as well as 45 related cell cultures. We assayed these samples via exome-seq and/or high-resolution droplet digital PCR, allowing us to distinguish complex therapy-induced selection and drift processes among endogenous cancer subclones with cellularity uncertaint

Systems consequences of amplicon formation in human breast cancer

Chromosomal structural variations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural variations, we analyzed eight breast tumor samples with a focus on regions of gene amplification using mate-pair sequencing of long-insert genomic DNA with matched transcriptome profiling. We found that tandem duplications appear to be early events in tumor evolution, especially in the genesis of amplicons. In a detailed reconstruction of events on chromosome 17, we found large unpaired inversions and deletions connect a tandemly duplicated ERBB2 with neighboring 17q21.3 amplicons while simultaneously deleting the intervening BRCA1 tumor suppressor locus. This series of events appeared to be unusually common when examined in larger genomic data sets of breast cancers albeit using approaches with lesser resolution. Using siRNAs in breast cancer cell lines, we showed that the 17q21.3 amplicon harbored a significant number of weak oncogenes that appeared consistently coamplified in primary tumors. Down-regulation of BRCA1 expression augmented the cell proliferation in ERBB2-transfected human normal mammary epithelial cells. Coamplification of other functionally tested oncogenic elements in other breast tumors examined, such as RIPK2 and MYC on chromosome 8, also parallel these findings. Our analyses suggest that structural variations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously and that such oncogenic cassettes are favored during the evolution of a cancer.Singapore. Agency for Science, Technology and ResearchNational Science Foundation (U.S.) (East Asia and Pacific Summer Institutes (OISE-1108282)

Global analysis of gene expression in NGF-deprived sympathetic neurons identifies molecular pathways associated with cell death

Developing sympathetic neurons depend on nerve growth factor (NGF) for survival and die by apoptosis after NGF withdrawal. This process requires de novo gene expression but only a small number of genes induced by NGF deprivation have been identified so far, either by a candidate gene approach or in mRNA differential display experiments. This is partly because it is difficult to obtain large numbers of sympathetic neurons for in vitro studies. Here, we describe for the first time, how advances in gene microarray technology have allowed us to investigate the expression of all known genes in sympathetic neurons cultured in the presence and absence of NGF

Italiano inclusivo: dalle Raccomandazioni di Alma Sabatini alle riflessioni LGBTQ+

Dalla pubblicazione delle "Raccomandazioni per un uso non sessista della lingua italiana" di Alma Sabatini, nel 1987, si è diffusa anche in Italia la discussione sul sessismo nella pratica linguistica. A distanza di trent'anni rimane acceso il dibattito attorno alla visibilità femminile nella lingua, in particolare per quanto riguarda i nomi di professioni prestigiose o cariche istituzionali che incontrano, ancora, avversione e critiche. La riflessione è però andata oltre al solo genere femminile e si è cominciato a riflettere su come rappresentare tutti i genere nella lingua. Grazie, infatti, alle teorie anti-essenzialiste di Judith Butler si comprende ora che il genere non è prodotto di un'essenza pre-esistente in natura, ma piuttosto una costruzione sociale e culturale. Per questo motivo, si vede oggi che il binario di genere uomo-donna non è più adeguato a riflettere la realtà, ma che ci sono molteplici interpretazioni del genere e della propria identità di genere. Una di queste è l'identità di genere non-binaria, da cui scaturisce il bisogno di alternative rispetto alle desinenze standard maschile e femminile. Sono perciò comparse varie proposte, tra cui lo schwa, che sta attualmente prendendo piede nell'ambiente attivista italiano e che, in seguito alla decisione di un comune emiliano di usarlo nelle proprie comunicazioni social, è stato anche oggetto di attenzioni da parte di giornali e riviste, che non hanno risparmiato le critiche e le beffe, tanto nei confronti dello schwa quanto delle istanze dell'inclusività linguistica

Reply to Watkins et al.: Whole-genome sequencing-based identification of diverse tandem duplicator phenotypes in human cancers.

Proc Natl Acad Sci U S A 2016 Sep 6; 113(36):E5259-60